Regulation of Glioblastoma Stem-Like Cells by CDC20-Anaphase-Promoting Complex

摘要 胶质母细胞瘤是成人中最常见的恶性原发性脑肿瘤，并且总是致命的。胶质瘤 干细胞样细胞（GSC）代表胶质母细胞瘤细胞的动态亚群，现在已知其 表现出治疗抗性并导致肿瘤复发。因此，了解管理机制 GSC状态对于开发针对胶质母细胞瘤有效疗法至关重要。使用患者来源的 在胶质母细胞瘤细胞系中，我们最近发现了E3连接酶CDC 20-后期- 促进复合物（CDC 20-APC）在GSC的侵袭、自我更新和肿瘤起始的关键功能中的作用。 此外，我们已经确定了多能性调节转录因子SOX 2作为一种新的CDC 20 - 21。 相互作用蛋白，其在体外介导⑶ C20-APC在GSC中的下游作用。到底是怎么回事 CDC 20-APC/SOX 2信号通路在GSC中受到调节，以及CDC 20-APC/SOX 2通路在GSC中的作用 在体内胶质母细胞瘤中的作用仍有待确定。我们的目标是：1）确定分子 CDC 20-APC/SOX 2通路在GSC侵袭中的潜在机制，2）确定 CDC 20-APC/S 0X 2通路在体内胶质母细胞瘤中对肿瘤起始和维持的作用，和3） 确定CDC 20-APC/SOX 2通路对GSC对标准治疗反应性的影响 替莫唑胺化疗和放射治疗。该项目的长期目标是开发新的 CDC 20-APC-导向的治疗策略，以破坏GSC状态并增强目前的治疗效果。 治疗。

ABSTRACT Glioblastoma is the most common malignant primary brain tumor in adults and is invariably fatal. Glioblastoma stem-like cells (GSCs) represent a dynamic subpopulation of glioblastoma cells, which are now known to exhibit treatment resistance and cause tumor recurrence. Therefore, knowledge of the mechanisms governing the GSC state is essential to develop effective therapies against glioblastoma. Using patient-derived glioblastoma cell lines, we have recently uncovered a requirement for the E3 ligase CDC20-Anaphase- Promoting Complex (CDC20-APC) in key GSC functions of invasion, self-renewal, and tumor initiation. Furthermore, we have identified the pluripotency regulatory transcription factor SOX2 as a novel CDC20- interacting protein, which mediates the downstream effects of CDC20-APC in GSCs in vitro. How exactly the CDC20-APC/SOX2 signaling pathway is regulated in GSCs and what role the CDC20-APC/SOX2 pathway plays in glioblastoma in vivo remain to be defined. The goals of our proposal are: 1) to identify the molecular mechanisms underlying the CDC20-APC/SOX2 pathway in GSC invasiveness, 2) to determine the impact of the CDC20-APC/SOX2 pathway on tumor initiation and maintenance in glioblastoma in vivo, and 3) to determine the effect of the CDC20-APC/SOX2 pathway on GSC responsiveness to standard-of-care chemotherapy temozolomide and radiation therapy. The long-term goal of this project is to develop novel CDC20-APC-directed therapeutic strategies to disrupt the GSC state and enhance the effectiveness of current treatments.